The present invention is directed to efficient multistep processes for the preparation of compounds of the formula (6) and (6'), as shown in Scheme 3 below; and to certain of the intermediates, specified by the general formulas (8) and (9) below, which find special value in these multistep processes. The compounds of the formulas (6) and (6') are useful as precursors of the various penem antibiotics specified by the formula (7) and (7'), also shown in Scheme 3 below.
Heretofore, a number of processes have been reported for the preparation of penem antibiotics substituted at the 2-position with an alkyl group or a thioether group, --SR.sup.2, as found in the formulas (6), (6'), (7) and (7') below. For thioether compounds (6) and (7), two of the more general of these processes are illustrated in Schemes 1 and 2. In Scheme 1, an alternative intermediate to the silver salt of the mercaptan is the mercaptan itself, reportedly obtained by Zn/H.sup.+ reduction of the tritylated thiol (Girijavallabhan et al., J. Antibiotics 39, 1182 (1986); U.S. Pat. No. 4,584,133). Menard et al., U.S. Pat. No. 4,272,437, has also described processes related to those of Scheme 2, which were applied more generally to the synthesis also of the compounds (6') and (7'). For example intermediates of the type (K) are reacted with an acylating agent such as EQU R.sup.5 R.sup.6 CH--COCl
to form compounds structurally related to (L), which in turn are heated to close the ring and thus form said compounds (6') and (7'). See also published application EP No. 199,446, where compounds of the type (6') and (7') below in which R.sup.5 and R.sup.6 are taken together are similarly prepared. ##STR1##
References:
Girijavallabhan et al., J. Antibiotics 39, 1182 (1986); U.S. Pat. No. 4,584,133, wherein ##STR2## R.sup.e =--CH.sub.2 CH.dbd.CH.sub.2, R.sup.f =beta-naphthyl, ##STR3## etc., X.sup.a =leaving group. DiNinno et al., U.S. Pat. No. 4,610,823 (1986); Leanza et al., Tetrahedron 39, 2505 (1983), wherein ##STR4## R.sup.g =alkyl, aralkyl, etc., X.sup.a =leaving group. PA0 (a) Hamanaka, U.S. Pat. No. 4,614,737; PA0 (b) Girijavallabhan et al., U.S. Pat. No. 4,614,738; PA0 (c) Hamanaka, U.S. Pat. No. 4,619,924; PA0 (d) Girijavallabhan et al., U.S. Pat. No. 4,443,463; PA0 (e) Girijavallabhan et al., U.S. Pat. No. 4,530,793; PA0 (f) Girijavallabhan et al., U.S. Pat. No. 4,584,133; PA0 (g) Ganguly et al., U.S. Pat. No. 4,690,922; PA0 (h) McCombie, European published application No. 61,205; PA0 (i) Hamanaka, European published application No. 132,101; PA0 (j) Hamanaka, European published application No. 138,539; PA0 (k) Perrone et al., European published application No. 199,490; PA0 (l) Takemura et al., European published application No. 210,883; PA0 (m) Kirkup et al., European published application No. 238,285; PA0 (n) Sunegawa et al., European published application No. 243,686; PA0 (o) McCombie et al., European published application No. 257,602; and PA0 (p) DiNinno et al., Tetrahedron Letters No. 3535 (1982).
See also Girijavallabhan et al., U.S. Pat. Nos. 4,443,373 and 4,530,793 for an alternative synthesis of the compounds (E), wherein R.sup.d is CH.sub.3 CHOH-- and R.sup.e is CH.sub.2 CH.dbd.CH.sub.2 or CH.sub.2 CH.sub.2 OSi(CH.sub.3).sub.3, from the compound (A). ##STR5##
*These steps assumed on the basis of the footnote 16 reference to U.K. No. 2,042,514.
Reference:
DiNinno et al., Tetrahedron Letters 23, 3535 (1982), wherein: ##STR6## --CH.sub.2 CH.sub.2 OH, etc.
See also Ganguly et al., J. Antimicrob. Chemo. 9, Suppl. C1, (1982) using several similar steps in a different sequence.
Ghosez et al., Tetrahedron Letters 39, 2493 (1983) have described the synthesis of 2-oxopenams from penicillin G and the conversion of same to 2-alkoxypenem derivatives of penicillin G. Japanese Kokai No. 84-115,788 (Chem. Abst. 96:34979y, Derwent Abst. 78700D) similarly describes conversion of hydroxy and carboxy protected 6-(1-hydroxyethyl)-2-oxopenams to the corresponding alkoxy analogs.
Additional, alternative methods for the synthesis of penems include those described by Dextraze et al., U.S. Pat. No. 4,769,451; Pirie et al., U.S. Pat. No. 4,751,297; Volkmann et al., U.S. Pat. No. 4,739,047; Brighty, U.S. Pat. No. 4,695,626; Brighty et al., U.S. Pat. No. 4,782,145; Perrone et al., J. Org. Chem., 51, 3413 (1986); Batastini et al., U.S. Pat. No. 4,631,150; UK Patent application No. 2,187,448; Alpegiani et al., U.S. Pat. No. 4,577,016; and Franceschi et al., J. Antibiotics 36, 938 (1983).
There have been numerous reports in the literature concerning the conversion of 2-oxocarbapenams and 3-oxocephams to 2-(alkylthio)-2-carbapenems and 3-alkylthio-3-cephems via enolic esters: ##STR7## where R.sup.h is a conventional carboxy protecting group, R.sup.i is, for example, diphenyl- or diethylphosphoryl, tosyl, mesyl, or trifluoromethanesulfonyl. See for example Sletzinger et al., Tetrahedron Letters 21, 4221 (1980); Andrus et al., J. Am. Chem. Soc. 106, 1808 (1984); Evans et al., Tetrahedron Letters 26, 3787 (1985), and 27, 3119 (1986) and U.S. Pat. No. 4,673,737; Ratcliffe et al., 21, 31 (1980); ibid. 1979, 4947; Salzmann et al., ibid. 21, 1193 (1980); Melillo et al., ibid. 21, 2783 (1980); Iimori et al., and J. Am. Chem. Soc. 105, 1659 (1983). However, the chemistry observed with these carbapenem ketone groups has been generally inapplicable to the thiolactone carbonyl group of 2-oxopenems. For example, the reaction of mesyl chloride or mesyl anhydride with a compound of the type (4) below produces a compound of the type ##STR8## while either tosyl chloride or triflyl chloride and a compound of the type (4) produces a compound of the type: ##STR9## More recently it was specifically reported in published European patent application No. 257,419 that a compound of the type (4) below was reacted with diphenylphosphoryl chloride to form the diphenylphosphoryl ester in situ, which was in turn reacted with a phenol to form a compound of the type ##STR10## in very low yield. This application offers no specific support for the asserted broader use of other potential enol ester forming reagents such as triflyl chloride, which is in fact a known chlorinating agent, not a triflate ester forming reagent (vide supra; and Hakimelahi et al., Tetrahedron Letters, 1979, pp. 3643-3644).